MPGN Flashcards
MPGN
Epidemiology
MPGN is a glomerular injury pattern common to a heterogeneous group of diseases.
Most commonly presents in childhood but can occur at any age
MPGN
Epidemiology
Accounts for 7% to 10% of all cases of biopsy-confirmed GN
Third or fourth leading cause of ESRD among primary GN
MPGN
Histopathology
LM:
Mesangial hypercellularity, endocapillary proliferation, and capillary wall remodeling (with formation of double contours), all leading to lobular accentuation of glomerular tufts (chunky segments/pieces)
MPGN
Histopathology
LM:
Glomerular changes are due to deposition of complement factors with or without immunoglobulins in the glomerular mesangium and along capillary walls.
MPGN
Histopathology
EM:
Subendothelial deposits with mesangial migration and interposition with duplication of basement membrane forming capillary double contours, variable mesangial deposits, subepithelial and intramembranous deposits in type III MPGN.
MPGN
Histopathology
Traditional classification of MPGN was based on EM findings:
MPGN I: subendothelial deposits
Idiopathic
Secondary causes: subacute/chronic infections, hepatitis C > B, cryoglobulinemia, lymphoproliferative malignancies, carcinomas, C2 or C3 deficiency, autoimmune disease, C3 glomerulopathy
MPGN
Histopathology
Traditional classification of MPGN was based on EM findings:
MPGN III: MPGN type I features with additional subepithelial and/or intramembranous deposits.
MPGN
Histopathology
Traditional classification of MPGN was based on EM findings:
MPGN II: dense deposits in GBM, a.k.a. “dense-deposit disease,” “DDD”
Idiopathic
Secondary causes: complement dysregulation due to deficiency or mutations of complement regulatory proteins, autoantibody formation against regulatory proteins, C3 nephritic factor autoantibodies (C3NeF), familial and acquired partial lipodystrophy
MPGN
Histopathology
Traditional classification of MPGN was based on EM findings:
MPGN I and MPGN III may be either immune complex–mediated or complement-mediated GN.
MPGN
Histopathology
Traditional classification of MPGN was based on EM findings:
IF: Findings from IF studies may define the underlying pathogenesis of the MPGN.
MPGN
Histopathology
Traditional classification of MPGN was based on EM findings:
NOTE
Current classification of MPGN is based on its underlying pathogenesis as immune complex-mediated, complement-mediated, or neither.
MPGN
Histopathology
Immune Complex–Mediated MPGN:
Involves classical pathway
IF typically shows both Ig and complement deposits.
MPGN
Histopathology
Immune Complex–Mediated MPGN:
Proposed sequence of events:
Chronic increase in immunoglobulin production due to infections, autoimmune disease, or monoclonal gammopathies leads to:
Binding of the immunoglobulins to GBM and activation of the complement cascade and induction of inflammatory changes (cellular or proliferative), followed by a:
MPGN
Histopathology
Immune Complex–Mediated MPGN:
Proposed sequence of events:
Reparative phase where new mesangial matrix is formed (mesangial expansion) along with new GBM formation (duplication of GBM “tram tracks or double contours”).
MPGN
Histopathology
Immune Complex–Mediated MPGN:
Proposed sequence of events:
New GBM formation may entrap capillary wall deposits ± inflammatory cells, mesangial, and endothelial cells, leading to thickened appearance of capillary walls and formation of double contours along capillary walls.
MPGN
Histopathology
Immune Complex–Mediated MPGN:
Conditions leading to increased Ig production:
Infections: chronic viral infections (e.g., hepatitis C»_space; B ± cryoglobulins); bacterial infections (endocarditis, shunt/indwelling catheter nephritis, abscesses; common organisms: Staphylococcus, Mycobacterium tuberculosis, streptococci, Propioibacterium acnes, Mycoplasma pneumoniae, Brucella, Coxiella burnetii, Nocardia, Meningococcus; fungal infections, parasitic infections.
MPGN
Histopathology
Immune Complex–Mediated MPGN:
Conditions leading to increased Ig production:
Autoimmune diseases: systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, mixed connective tissue diseases
Paraproteinemias: monoclonal gammopathies ± cryoglobulins
MPGN
Histopathology
Complement-Mediated MPGN:
Involves complement dysregulation in the alternative pathway
MPGN
Histopathology
Complement-Mediated MPGN:
Dysregulated complement activation leads to abnormal C3 convertase activity and resultant inflammatory changes, endothelial/GBM/podocyte injury, and subsequent reparative phase similar to that seen with immune complex–mediated injury. With the exception of DDD, EM cannot distinguish between immune complex–mediated and complement-mediated MPGN.
MPGN
Histopathology
Complement-Mediated MPGN:
Dysregulation of complement activation may occur via different mechanisms:
Antibody formation against:
C3 convertase (antibodies against C3 convertase are also known as C3 nephritic factor (C3NF)—C3NF binds to and stabilizes C3 convertase, thereby prolonging its half-life and allowing continuing activation of the alternative pathway.
Complement regulators (Factor H, I, or B)
MPGN
Histopathology
Complement-Mediated MPGN:
Dysregulation of complement activation may occur via different mechanisms:
Mutations of complement regulators: factor H, factor I, membrane cofactor protein MCP/CD46, complement factor H-related protein CFHR5, CFHR 3-1
Allele variants: C3, MCP
MPGN
Histopathology
Complement-Mediated MPGN:
Dysregulation of complement activation may occur via different mechanisms:
Dysregulation of alternative pathway may be subdivided into DDD and C3 glomerulonephritis (C3GN) based on EM findings. Both disease entities, however, are thought to be part of a continuum of the same condition.
MPGN
Histopathology
Complement-Mediated MPGN:
Dysregulation of complement activation may occur via different mechanisms:
Differences in histopathology are likely due to the degree or site, or both, of the dysregulation of the alternative pathway. Certain allele variations of complement regulating proteins may be associated with DDD, while others (e.g., CFHR5) with C3GN.
MPGN
Histopathology
Complement-Mediated MPGN:
Dysregulation of complement activation may occur via different mechanisms:
DDD: Characterized by osmiophilic, sausage-shaped, wavy, dense deposits that replace GBM and also occur in mesangium (old classification: MPGN II). MPGN II is associated with partial lipodystrophy and ocular drusen.
MPGN
Histopathology
Complement-Mediated MPGN:
Dysregulation of complement activation may occur via different mechanisms:
C3GN is characterized by mesangial, subendothelial, and sometimes subepithelial and intramembranous deposits (old classification: MPGN I or MPGN III).
MPGN
Histopathology
MPGN without IC or complement:
May be seen with thrombotic microangiopathies (TMA)
Pathologic characteristics: absence of immunoglobulins or complements on IF; absence of electron-dense deposits in mesangium or capillary walls on EM
MPGN
Histopathology
MPGN without IC or complement:
Associated conditions: thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome, atypical hemolytic-uremic syndrome, antiphospholipid antibody syndrome, drug-induced TMA, malignant hypertension, radiation nephritis, bone marrow transplant-associated nephropathy, connective tissue disorders
MPGN
Clinical Manifestations
Asymptomatic hematuria and proteinuria
Acute nephritic syndrome
MPGN
Clinical Manifestations
Nephrotic syndrome
CKD
Rapidly progressive glomerulonephopathy
MPGN
Diagnosis
Complement levels:
IC-mediated MPGN: typically low C3 and low C4
Complement-mediated MPGN: typically low (but may be normal) C3 and normal C4
MPGN
Diagnosis
Serologies per kidney biopsy:
Immunofluorescence with both immunoglobulin and complement deposits:
Blood cultures, polymerase chain reaction and serologic tests for viral (e.g., hepatitis B, C, cytomegalovirus (CMV), bacterial, occult infections, malaria, and fungal infections (per local prevalence and/or symptoms)
MPGN
Diagnosis
Serologies per kidney biopsy:
Immunofluorescence with both immunoglobulin and complement deposits:
Cryoglobulins, (consider rheumatoid factor: 70% cross-reactivity with cryoglobulins)
Serum protein electrophoresis and immunofixation, serum free light chains
Screening for autoimmune disorders, particularly SLE
MPGN
Diagnosis
Serologies per kidney biopsy:
Immunofluorescence with complement deposits alone (with or without dense deposits on EM):
Evaluation of alternative pathway: serum complement levels, serum membrane-attack complex levels, alternative pathway functional assay, hemolytic complement assay
Retinal scan to evaluate for ocular drusen
MPGN
Diagnosis
Serologies per kidney biopsy:
Immunofluorescence with complement deposits alone (with or without dense deposits on EM):
Consider genetic analysis for mutations and allele variants of complement factors and assays for presence of autoantibodies to complement-regulating proteins, including C3 nephritic factor.
Evaluation of monoclonal gammopathy (particularly in older individuals)
MPGN
Diagnosis
Serologies per kidney biopsy:
Immunofluorescence with complement deposits alone (with or without dense deposits on EM):
Immunofluorescence without immunoglobulin or complement deposits: C3, complement factor H, ADAMST13, blood smear for schistocytes, LDH, indirect bilirubin, platelet count and volume
MPGN
Diagnosis
Serologies per kidney biopsy:
Management
Routine:
Use ACEI or ARB for proteinuria as safely tolerated.
Anticoagulation and antiplatelet therapy such as combination of aspirin plus dypiridamole are of unclear long-term benefit.
MPGN
Diagnosis
Specific therapy:
Idiopathic MPGN: all MPGN patients must be evaluated for secondary causes.
MPGN
Diagnosis
Specific therapy:
KDIQO suggests that patients with presumed idiopathic MPGN accompanied by nephrotic syndrome and decline in kidney function may be treated with either PO CYC or MMF and alternating or daily steroids, with initial therapy limited to 6 months.
MPGN
Diagnosis
Specific therapy:
Secondary MPGN: Treat underlying disease (i.e., infections, monoclonal gammopathy, autoimmune disease) if applicable.
Rituximab may be beneficial if monoclonal gammopathy but without overt hematologic malignancy.
Consider plasmapheresis if association with symptomatic cryoglobulinemia.
MPGN
Diagnosis
Specific therapy:
Glucocorticoids as monotherapy in adults: currently undefined
Rapidly progressive disease or crescentic glomerulonephritis: Limited data but may consider CNI, high-dose pulse steroids as monotherapy or in combination with AZA, CYC, or MMF.
MPGN
Diagnosis
Specific therapy:
MPGN due to complement dysregulation due to factor H abnormality or C3 nephritic factor autoantibody formation:
Glucocorticoids + cytotoxic agents
Consider plasmapheresis in severe cases.
MPGN
Diagnosis
Specific therapy:
MPGN due to congenital mutations leading to complement dysregulation:
Consider therapy that inhibits membrane attack complex (MAC) formation (e.g., eculizumab), particularly if high serum levels of MAC.
MPGN
Diagnosis
Specific therapy:
MPGN due to congenital mutations leading to complement dysregulation:
Eculizumab is an anti-C5 monoclonal antibody that inhibits C5 activation.
Eculizumab has been shown effective in the treatment of atypical HUS due to complement dysregulation in the alternative pathway.
Eculizumab may be effective in some patients with DDD.
MPGN
Kidney Transplantation
High recurrence rates: MPGN I (15% to 50%), DDD (80% to 100%)
DDD: universal recurrence (80% to 100%)
